1-Halo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines of the formula ##SPC1##
Wherein X is chlorine or bromine, R.sub.1 is hydrogen or C.sub.1 to C.sub.3 -alkyl, and the R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are hydrogen, C.sub.1 to C.sub.3 -alkyl, fluoro, chloro, bromo, nitro, cyano and trifluoromethyl, are known compounds being included in the description of U.S. Pat. No. 3,709,899. These compounds have sedative, tranquilizing and muscle relaxing properties in mammals and birds and they are useful as drugs where sedation, tranquilization or muscle relaxing effects are desired. These compounds are now also of interest for their use as intermediates in the preparation of the corresponding 2,4-dihydro-6-phenyl-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-ones by procedures now described in U.S. Pat. No. 3,856,809. Those '809 patented benzodiazepine-1-one derivatives have central nervous system sedative, transquilizing and antiolytic effects in mammals including humans, and a representative example thereof has been selected for study in humans in the clinic.
The process for preparing 1-halo-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepines described in U.S. Pat. No. 3,709,899 involves halogenation of the triazolobenzodiazepine with an N-halosuccinimide. However, that process requires the prior preparation of the triazolo-benzodiazepine which involves a multiplicity of process steps which, for economy reasons, chemical process operators would prefer to avoid.
U.S. Pat. No. 3,842,090 discloses a multi-step process for preparing a 1-substituted aminomethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Some of the steps thereof include the formation of a 2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone, and later in the process, reacting the 2-[1-(substituted aminomethyl)-3-(phthalimidomethyl)-triazol-4-yl]benzophenone with hydrazine hydrate to give the 1-(substituted amino)methyl-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine. However, at no time in that process is there a free halogen bonded to the 5-position of the triazole ring of the triazolobenzophenone derivative, so that patent does not describe or suggest the problem which has been solved by this invention.
In South African Pat. No. 74/0466 there is described a process for preparing 1-unsubstituted or 1-alkyl, 1-phenyl, 1-benzyl or 1-alkoxycarbonyl-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepines by heating a 2-[3-(phthalimidomethyl)-5-substituted-4H-1,2,4-triazol-4-yl]benzophenone with hydrazine hydrate in ethanol. However, there is no disclosure therein of using that process to cyclize products having a 5-halo-substituent on the triazole ring of the triazolylbenzophenone intermediate.
U.S. patent application Ser. No. 391,647, filed Aug. 27, 1973, now U.S. Pat. No. 3,891,666, describes a process for reacting a mixture of 5-chloro-2-(3-bromo-5-methyl-4H-1,2,4-triazol-4-yl)benzophenone with hydrazine or its mineral acid salt and a base in a lower alkanol, e.g., ethanol at 70.degree.-120.degree. C. to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,3,4]benzotriazepine, indicating that hydrazine reacts with halogen on the triazole ring of triazolylbenzophenone compounds.
Similarly, U.S. Pat. No. 3,880,878 describes the reaction of a 5-(substituted aminomethyl)-3-halo substituted triazole moiety on a triazolylbenzophenone with hydrazine or a hydrazine salt and a base at 70.degree. to 120.degree. C. to close the benzotriazepine ring and thus to obtain a 1-(substituted aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,3,4]benzotriazepine, indicating again the hydrazine reacts with triazole-ring-bound halogen in triazolylbenzophenone reactants to form triazolobenzotriazepine compounds.
From the above histroy of this process chemistry one would expect therefore that a process route involving the use of hydrazine and a halo-substituted triazolylbenzophenone should not be used to prepare halogen-substituted triazolobenzodiazepines because in doing so would be expected that the triazolo-ring-bound-halogen would react with the hydrazine, thus defeating the object or purpose of the reaction.